Period control of the coupled clock and cell cycle systems

Abstract

The mammalian clock and cell cycle are two essential biological oscillators. In this work we investigate the coupling of these oscillators via non-linear dynamical modeling. We use previously developed reduced models of these systems and study a molecular interaction of MPF (mitosis promoting factor) repression by the CLOCK:BMAL1 protein complex, via induction of the repressor wee1. Furthermore, we propose an hypothesis whereby the clock responds to cell cycle Growth Factors (GFs) via a pathway involving the non-essential cell cycle complex cyclin D/cdk4 and study this interaction in the context of unidirectional clock → cell cycle coupling. We observe 1:1, 3:2, 4:3, 5:4 ratios of clock to cell cycle period and identify GF and the coupling strength cb as decisive control parameters for the system's state of synchronization. Synchronization ratios differing from 1:1, namely 3:2 and 5:4, have been observed in cells treated with the corticosteroid Dexamethasone (Dex). Here, we study Dex application and are able to reproduce the induction of ratios differing from 1:1. Finally, because slowing down the cell cycle is very relevant in the context of cancer therapies, we devise particular protocols of cell cycle period control with the use of clock inputs that are successful in substantially slowing down the cell cycle by the use of the system's synchronization dynamics, obtaining 2:3, 3:4, 4:5 ratios of clock to cell cycle period.